Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair |
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Authors: | D'Angiolella Vincenzo Donato Valerio Forrester Frances M Jeong Yeon-Tae Pellacani Claudia Kudo Yasusei Saraf Anita Florens Laurence Washburn Michael P Pagano Michele |
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Institution: | 1 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA 2 Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8501, Japan 3 The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA 4 Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA 5 Howard Hughes Medical Institute |
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Abstract: | F-box proteins are the substrate binding subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes. Using affinity purifications and mass spectrometry, we identified RRM2 (the ribonucleotide reductase family member 2) as an interactor of the F-box protein cyclin F. Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), which are necessary for both replicative and repair DNA synthesis. We?found that, during G2, following CDK-mediated phosphorylation of Thr33, RRM2 is degraded via SCF(cyclin F) to maintain balanced dNTP pools and genome stability. After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. In summary, we have identified a biochemical pathway that controls the abundance of dNTPs and ensures efficient DNA repair in response to genotoxic stress. |
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